Composition and method for relieving spasticity



United States Patent C COMPOSITION AND METHOD FOR RELIEVING SPASTICITYDavid F. Marsh, Ilafayette Hill, Pa., and Joseph Sam, Syracuse, N.Y.;Audrey S. Marsh, executrix of the estate of said David F. Marsh,deceased No Drawing. Original application August 8, 1955, Serial No.527,145. 28, 1955, Serial No. 543,579

9 Claims. (Cl. 167-65) The present invention relates to a novel medicalpreparation for the relief of spasticity and to a method for relievingspasticity. The present application is a division of application SerialNo. 527,145, filed August 8, 1.955, and now abandoned.

Spasticity is an uncontrolled, involuntary, excessive contraction of oneor more skeletal muscles and is a major component of many common diseaseconditions. It has been difiicult if not impossible to relieveclinically. The manifestations of spasticity range in severity fromthose observed in minor transient injuries to localized areas, such assprains and strains, through more serious conditions, such as chroniclow back pain (lumbago), rheumatoid arthritis and rheumatoid spondylitisto the very severe incapacitating neurological diseases, such asmultiple sclerosis, Parkinson's disease, cerebral palsy, and the like.

Mephenesin is known to relieve, in animals, experimentally inducedspasticity, that is, to produce relaxation of the skeletal muscles, by amechanism involving the depression of the polysynaptic pathways of thecentral nervous system. The activity of this compound is so low and theduration so brief, that it is not feasible to employ this materialclinically for the relief of spasticity. In addition, as is known, theadministration of this material produces undesirable side effects, suchas initial excitement, salivation, nausea and vomiting. There are alsocertain other compounds, discussed in the literature, which are statedto possess this ability to relax skeletal muscles. These compoundsinclude 2- amino-benzoxazole, 2-amino-5-chorobenzothiazole and2-amino-6-methylbenzothiazole. However, these compounds also produce theundesirable effects mentioned above even at the dose levels insufficientto produce muscular relaxation. (L. S. Goodman and A. Gilman, pp.206-208, The Pharmacological Basis of Therapeutics, second ed., 1955,the Macmillan Co., New York.)

It is the principal object of the present invention to provide novelcompositions possessing valuable thera peutic properties, that is, theability to produce relaxation of the skeletal muscles by a mechanisminvolving the depression of the polysynaptic pathways of the centralnervous system and thus the ability to relieve spasticity in animals andman.

It is another object of the invention to provide novel medicalpreparations which possess the beneficial action on the central nervoussystem referred to above, without, however, deleterious side effects,such as initial excitement, salivation, nausea or vomiting.

Still another object of the present invention is to provide novelmedical preparations capable of producing, at reasonable doses, usefulrelaxation of skeletal muscles for substantial periods of time and whichpossess a wide margin between the efiective dose and the lethal dose.

A further object is to provide a novelmethod for relieving spasticity inanimals and man.

Other objects, including the provision of means for preparing the novelcompositions, will become apparent Divided and this application OctoberICC from a consideration of the following specification and claims.

The composition of the present invention comprises a benzoxazolecompound selected from the group consisting of2-amino-5-chlorobenzoxazole and salts thereof, and a pharmaceuticalcarrier.

The compositions of the present invention have been found to producerelaxation of the skeletal muscles by a mechanism involving thedepression of the polysynaptic pathways of the central nervous system.That is to say, the compositions prevent or overcome hypertonia andhyperflexia by selective depression of subcoitical and spin polysynapticpathways. Compared to mephenesin, the present compositions are at leastfour times as active in producing relaxation when given orally, have anexceptionally long duration of action (up to 24 hours in therapeuticdoses), have a wide safety marg n between effective dose and lethaldose, and lack any significant side effects, including initialexcitement, salivation, nausea or vomiting. The compositions maytherefore be readily employed for the relief of spasticity in animalsand man. Of special importance is the fact that the compositions arehighly eifective orally, and thepreferred compositions are, therefore,adapted for oral administration such as in the form of suspension,capsule or tablet dosage form. As will appear hereinafter, numeroustests have been made using compositions of the invention in variousspecies of animals and in man from which it is evident that thecompositions are highly effective in the relaxation, of the skeletalmuscles and are safe.

The Z-amino-5-chlorobenzoxazole may be prepared by the removal ofhydrogen sulfide from 5 -chloro-2-hydroxyphenylthiourea in accordancewith the procedure disclosed and claimed in copending application SerialNo. 527,883, filed August 11, 1955, and now Patent No. 2,780,633, issuedFebruary 7, 1957. A specific example of the preparation of the compoundin accordance with that procedure is as follows:

Example A Sixty-one grams of 5-chloro-2-hydroxyphenylthiourea are mixedwith grams(0.65 mole) of yellow lead oxide and one liter of methanol.The mixture is refluxed with stirring for three hours. The lead sulfidewhich is formed and the excess lead oxide are removed by filtration andwashed with methanol. The methanol solutions are combined, anddistillation of the methanol under vacuum, leaves, as residue, crude2-amino-5-chlorobenzoxazole. Recrystallization several times frombenzene results in White crystals melting at -1855 C.

The calculated analysis for C H ClN O is C, 49.9; H, 3.0; Cl, 21.0; andN, 16.6; that found is C, 49.5; H, 3.2; Cl, 20.9 and N, 16.5.

An ultraviolet spectrum of a solution of 2 milligrams of the compoundper 100 milliliters of methanol shows peaks at 244 and 285 mu.

A specific example of the preparation of S-chloro-Z-hydroxyphenylthiourea is as follows:

Example B To a solution of 106 grams (0.74 mole) of 2-amino-4-chlorophenol in 500 milliliters of water containing 69 ml. ofconcentrated hydrochloric acid (29.2 grams, 0.8 mole) are added 60.8grams (0.8 mole) of ammonium thiocyanate. The solution is placed in anevaporating dish and heated on a steam bath for 5 hours. The solid whichresults is then removed from the concentrated solution by filtration,washed with a small amount of water and dried. The filtrate is placed inan evaporating dish and heated on a water bath for two hours. At the endof this time, the mixture is cooled, and the solid which precipitatesout is removed by filtration. -=Both solid products are .chloro2-hydroxyphenylthiourea and maybe combined.

The 2-amino-5-chlorobenzoxazole may also be prepared by aminating thecarbon atom in the number 2 position of 5.-c hlorobenzoxazole -inaccordance with the procedure disclosed and claimed in copendingapplication'Serial No'. 527,884,.f1led August 11, 195-5, and nowabandoned. A specific example of the preparation of the compound by thisprocedure is as follows:

Example C A slurry of 2 grams of 2,5-.dichlorobenzoxazole in 20 'ml. of28% aqueous ammonia is shaken vigorously for about an hour until all thedichloio compound has reacted. The solid 2-amino-5-chlorobenzoxazole isthen filtered .ofi andwashed Swith'wa'ter. To hasten .the reaction, themixture maybe heated gently under a reflux condenser during the stirringperiod; the heating not being siiflicient to drive oifsubstantialamounts .of ammonia he tore the reaction is completed.Crystallization of the solid product from benzene g'ives2-amino-5-chlorobenzoxazole melting at 185-186 Ultraviolet spectrumanalysis in .inethanol shows peaks at 245 and 286 mu."

The. Z amino-5-chlorobenzoxazole possesses basic prop- ;ertics enablingit to form addition s'alts with acids. Hence this .compound may beemployed either as the base or as a salt. The acid forming the salt maybe any inorganic or organic acid producing a pharmaceutically acceptable.salt, for example, hydrochloric,hydrobromic, hydriodic, nitric,sulfuric, phosphoric, and the like; acetic, propionic, caproic, stearic,and other acids of this series, and the like; crotonic,'fumaric, oleic,citric, tartaric, lactic, ben- .zoic, .naphthoic, salicylic, methanesulphonic, camphor .sulphonic, and the like.

If a salt is employed, the salt will be pharmaceutically acceptable andany toxicity or other undesirable effects whichrnay .be imparted shouldbe taken into consideration as well known in the art. Pharmaceuticallyuseful salts should not be substantially more toxic than the compounditself and should be able to be incorporated in liquid or solid.pharmaceutical'media for the preparation of therapeutically usefulcompositions.

In preparing the compositions of the present invention the benzoxazolecompound will-be combined with a significant amount of a pharmaceuticalcarrier. The carrier may take a wide variety'of forms depending upon theform of the preparation desired for administration. For parenteralinjection the carrier may be sterile water with suitable adjustment ofthe pH to insure solution of the -benzoxazole compound. For example,'thecompound not in-salt form is practically insoluble in water while thesalts vary in solubility, and in some cases the solubility of a salt isnot sufi'icient to provide the desired concentration. In this case thepH may be further adjusted. Thus when using the hydrochloride, forinstance, in water, the pH will be further adjusted by the addition ofacid to main- .tain the compound in solution. As stated, the preferredform of administration of the present composition is oral, and the oraldosage may be in the 'form of a suspension, powder adapted forsuspension in liquid media, tablet or capsule. In preparing thecompositions in oral dosage form any of the usual pharmaceutical carriermedia may be employed, such as gelatinfin the caseof capsules; sterileWater, glycols, oils, alcohols, and the like in the case of suspensions;starches, sugars, kaolin, salts, lubri- 'cants, binders, and the like inthe case of powders and tablets. Tablets represent the most advantageousoral dosage form. i

The amount of the composition administered and the amount ofbenzoxazole' compound in the composition may vary somewhat dependinguponthe severity of the spastioity and upon the species being treated.As far as administration is concerned, the amount of compositionadministered may range from that providing as little as about -2milligrams of the benzoxa'zole compound per kilogram of body weight tothat providing as high as about milligrams per kilogram, preferably inthe case of humans, that providingbetween about 5 and about 40milligrams of benzoxazole compound per kilogram of body Weight. In thecomposition, the concentration of the benzoxazole compound should be atleast about 1%, by weight, preferably at least about 2%. Theconcentration of the benzoxazole compound may vary widely above thesefigures depending upon the form thecomposition takes, and in somecasesthe concentration of the benzoxazole compound may go as high asabout'8090%. Depending also upon the severity of the spasticity and uponthe species :being treated, as stated, the amountof benzoxazole compoundper dosage ..unit form may also vary widely. Generally, the compositionsper dosage unit will contain at least about 25 milligrams of thebenzoxazole compound, and in some ca s'es, such as in compositions forthe treatment of large domestic animals, like horses, the amount perdosage unit may reach as high as about 10,000 milligrams. In the case ofcompositions adapted for human administration, the amount will generally range between about 100 and about 1000 milligrams of benzoxazolecompound per dosage unit. Compositions of the present invention havebeen administered intraperitoneally, in the form of a 2% aqueoussolution of the 2-amino S-chlorobenzoxazole with sufiicient hydrochloricacid to provide a pH of 1.3, to albino mice; intraperitoneally, in theform of a 2% suspension of the 2-amino-S-chlorobenzoxazoie in a solutioncontaining 8.6% polyethylene glycol 300, 0.5% sodium carboxymethylcellulose and the remainder water, to albino mice, to albino rats and tohamsters; intravenously, in the form of the above-stated suspension towhich sufficient hydrochloric acid is added to provide a pH of l.'8*2.lthereby forming a solution of the Z-amino-S-chlorobenzoxazole, to albinorabbits; orally, in the form of the above-stated suspension and ascapsules imbedded in raw liver, to dogs; as well as orally,intravenously and intraperitoneally to cats and intraperitoneally toguinea pigs, demonstrating and confirming the marked ability to relaxskeletal muscles at levels not providing undesirable'side efiects.

'In addition to the above, other investigations of 2-amino-S-chlorobenzoxazole are reported in Fed. Proc. 14, page 356, March1955, by K. Kamijo and G. B. Koclle; in Fed. Proc. 14, page 341, March1955, by W. H. Funderburk and R; T. Woodcock; and in Proc. Soc. Exper.Biol.

and Med., 88, page 565, April i955, by K. Karniio and G. B. Koelle.

The following examples illustrate the preparation of typicalcompositions of the present'invention in oral dosage unit form. i

' Example I The following formula is for preparing 8000 tablets (10grains) each containing 250 mg. of 2-,amino-5-chlorobenzoxazole:

Z-amino-S-chlorobenzoxazole g 2000 Milk 'sugar'" -Q. g 800 Dibasiccalcium phosphate U.S.-P. g 1527.2 Starch (filler'and distintegratingagent) "g 799.3 Calcium stearate g 56.7 Gelatin solution pounris pergallon" 1.5

In place of the milk sugar, dibasic calcium phosphate and the portion ofthe starch making up the filler, there may be used sucrose, polyethyleneglycol 4000, mannitol and/or calcium carbonate in various combinationsand proportions. Starch paste, acacia solution, glucose solution,carboxymethylcellulose solution, shellac, or the like may be used inplace of gelatin solution as granulating agent. Calcium stearate isemployed as lubricating agent and may be replaced by magnesium stearate,stearic acid, talc or the like.

Example 11 The following formula may be employed for preparing mini 1-10,000 tablets (11.25 grains) each containing 500 mg. of2amino-5-chlorobenzoxa2ole:

2-amino-S-chlorobenzoxazole 11 lbs, 162 gr.

Milk sugar 1 1b., 13 02., 96 gr. Starch (filler) 1 lb., 13 02., 96 gr.Polyethylene glycol 4000 7 02., 24 gr.

Starch (disintegrating agent) 13 02., 340 gr. Calcium stearate l 02.,180 gr.

Gelatin solution 1.5 pounds per gallon.

Example 111 The following formula may be employed to make 1000 #3capsules each containing 100 mg. of Z-amino-S- chlorobenzoxazole:

Z-amino-S-chlorobenzoxazole g 100 sugar g 150 Fill Weight m2 250 Inplace of or in addition to the milk sugar may be used sucrose, dicalciumphosphate, calcium carbonate, kaolin, mannlitol and/ or starch, and thelike.

Example IV The following formula may be employed for preparing asuspension containing 250 mg. of 2-amino-5-chlorobenzoxazole per cc.:

Water, q.s.a.d. 1000 cc.

'In place of the propylene glycol may be used polyethylene glycol and/orglycerin'e. The carboxymethyl cellulose may be replaced by any one ofthe natural gums used as suspending agents. The parahydroxybenzoic acidesters may be replaced by any commonly used bacteriostatic agent, andother commonly used surface agents may be used in place of thepolyoxyethylene sorbitan monooleate.

Example V The following formula illustrates the preparation of asuspension containing 500 mg. per 5 cc. of 2-am1no-5- chlorobenzoxazole:

Z-amino-S-chlorobenzoxazole g 103 Carboxymethyl cellulose (lowviscosity, type 70) v 20 70% sorbitol solution g 250 Granulated sugar 5375 Propylene glycol g 50 Methyl ester of parahydroxybenzoic acid g 1.5Propyl ester of parahydroxybenzoic acid ..g 0.3 Polyoxyethylene sorbitanmonooleate g 0.5 Methyl salicylate 2.5

Water, q.s.a.d. 1000 cc.

Compositions of the type illustrated in Examples I-V ,6. have beenadministered, by the present time, to well over 200 patients. Theperiods of administration have been as long as eight weeks, and doses aslarge as 6 grams of benzoxazole a day have been used. Most patientsreceived 500 mg. or more three or four times a day. The administrationof these compositions has been found to produce a significant degree ofrelief from muscle stifiness, spasm and pain in patients with thefibrositic type of arthritic involvement and in rheumatoid spondylitis.The compositions also produce prompt symptomatic relief of a moderate toa marked degree from low back pain and muscle spasm, and have been shownto produce some relief of spasticity in severe neurological disorders.

Modification is possible in the selection of carrier material and in theamount thereof in preparing compositions in accordance with the presentinvention without departing from the scope thereof.

We claim:

1. A pharmaceutical composition comprising at least about 1%, by weight,of a 2-amino-5-chlorobenzoxazole compound selected from the groupconsisting of Z-amino- 5 -chloroben2oxa2ole and salts thereof, and apharmaceuti cal carrier.

2. A pharmaceutical composition comprising at least about 1%, by weight,of a Z-amino-S-chlorobenzoxazole compound selected from the groupconsisting of Z-amino- S-chlorobenzoxazole and salts thereof, and aliquid pharmaceutical carrier.

3. The product of claim 2 wherein said 2-amino-5- chlorobenzoxazolecompound is suspended in said liquid pharmaceutical carrier.

4. A pharmaceutical composition comprising at least about 1%, by weight,of a 2-amino-5-chlorobenzoxazole compound selected from the groupconsisting of Z-amino- 5-ch1orobenzoxazole and salts thereof, and asolid pharmaceutical carrier.

5. The product of claim 4 in tablet form.

6. A pharmaceutical composition in dosage unit form comprising, perdosage unit, at least about 25 milligrams of aZ-amino-5-chlorobenzoxazole compound selected from the group consistingof 2-amino-5-chlorobenzoxazole and salts thereof, and a pharmaceuticalcarrier.

7. The product of claim 6 containing between about and about 1000milligrams of Z-amino-S-chlorobenzoxazole compound per dosage unit.

8. A pharmaceutical composition comprising at least about 1%, by weight,of 2-amino-5-ch1orobenzoxa2ole and a pharmaceutical carrier.

9. A pharmaceutical composition comprising at least about 1%, by weight,of a salt of 2-amino-5-chlorobenzoxazole and a pharmaceutical carrier.

References Cited in the file of this patent UNITED STATES PATENTS SamFeb. 5, 1957 OTHER REFERENCES a. .AXLINE UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 2,890,985 June 16, 1959 David F.Marsh et a1,

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below,

In the grant, lines 2 and 3, for "Audrey S, Mwsh, executrix of theestate of said David F, Marsh, deceased," read assignors to McNeilLaboratories, Incorporated, of. Philadelphia, Pa.,, a corporation oiPennsylvania, 3 lines 12 and 13, for 'Joseph Sam, his heirs or assigns,and Audrey S, Marsh, as executrix, her successors" read McNeilLaboratories, Incorporated, its successors g in the heading to theprinted specification lines 5 and 6, for "Audrey So March,

executrix oi the estate of said David F, Marsh, deceased read assignorsto McNeil Laboratories, Incorporated, Philadelphia, Pa a corporation ofPennsylvania 3 column 2, line 13, for "spin" read me spinal =-=a Signedand sealed this 17th dagv of November 1959 Attest: I I v ROBERT C.WATSON Attesting Officer Conniissioner of Patents

1. A PHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ABOUT 1%, BY WEIGHT,OF A 2-AMINO-5-CHLOROBENZOXAZOLE COMPOUND SELECTED FROM THE GROUPCONSISTING OF 2-AMINO5-CHLOROBENZOXAZOLE AND SALTS THEREOF, AND APHARMACEUTICAL CARRIER.